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WO2008017989A1 - Dérivés de l'acide (3-amino-1,2,3,4-tétrahydro-9h-carbazol-9-yl)-acétique - Google Patents

Dérivés de l'acide (3-amino-1,2,3,4-tétrahydro-9h-carbazol-9-yl)-acétique Download PDF

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Publication number
WO2008017989A1
WO2008017989A1 PCT/IB2007/053046 IB2007053046W WO2008017989A1 WO 2008017989 A1 WO2008017989 A1 WO 2008017989A1 IB 2007053046 W IB2007053046 W IB 2007053046W WO 2008017989 A1 WO2008017989 A1 WO 2008017989A1
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Prior art keywords
tetrahydro
carbazol
fluoro
acetic acid
phenyl
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PCT/IB2007/053046
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English (en)
Inventor
Heinz Fretz
Julien Pothier
Philippe Risch
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Actelion Pharmaceuticals Ltd
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Priority to ES07805287T priority Critical patent/ES2374321T3/es
Priority to AU2007282949A priority patent/AU2007282949B8/en
Priority to DK07805287.5T priority patent/DK2051962T3/da
Priority to KR1020097004370A priority patent/KR101411820B1/ko
Priority to CN2007800292169A priority patent/CN101500996B/zh
Priority to MX2009001105A priority patent/MX2009001105A/es
Priority to EP07805287A priority patent/EP2051962B1/fr
Priority to CA2658986A priority patent/CA2658986C/fr
Priority to SI200730818T priority patent/SI2051962T1/sl
Priority to AT07805287T priority patent/ATE530523T1/de
Priority to US12/376,932 priority patent/US8143304B2/en
Priority to BRPI0715179-9A priority patent/BRPI0715179A2/pt
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to JP2009523396A priority patent/JP5220013B2/ja
Priority to NZ574705A priority patent/NZ574705A/en
Priority to PL07805287T priority patent/PL2051962T3/pl
Publication of WO2008017989A1 publication Critical patent/WO2008017989A1/fr
Priority to IL196891A priority patent/IL196891A/en
Priority to NO20090979A priority patent/NO20090979L/no
Priority to HK09110028.6A priority patent/HK1130062A1/xx
Priority to HR20120044T priority patent/HRP20120044T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to (3-amino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid derivatives of Formula I and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2 receptor (“DP receptor”) modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.
  • prostaglandin receptor modulators most particularly as prostaglandin D 2 receptor (“DP receptor”) modulators
  • such derivatives may be used alone or in pharmaceutical compositions for the treatment of both, chronic and acute allergic/immune diseases/disorders such as allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis, and basophil-related diseases, such as basophilic leukemia and basophilic leukocytosis, in humans and other mammals.
  • chronic and acute allergic/immune diseases/disorders such as allergic asthma, rhinitis
  • mast cells are activated and release chemotactic key mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D 2 (PGD 2 ).
  • TxA2 thromboxane A2
  • CysLTs cysteinyl leukotrienes
  • PPD 2 prostaglandin D 2
  • mediators interact with their respective receptors and cause physiological effects such as increased vascular permeability, edema, pruritus, nasal and pulmonary congestion, bronchoconstriction, and mucus secretion.
  • An increased vascular permeability for example, allows excessive infiltration of eosinophilic and basophilic leukocytes into the tissue and thus amplifies the allergic response.
  • Current treatments of allergic diseases comprise agents that can block or otherwise interrupt such interactions, e.g.
  • anti-histamines histamine Hl receptor antagonists
  • leukotriene receptor antagonists beta-adrenergic receptor agonists
  • corticosteroids corticosteroids
  • PGD 2 is an agonist known to act on two G-protein-coupled receptors, the PGD 2 receptor DPI and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as "DP2 receptor").
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • Elevated PGD 2 levels are considered to cause inflammation actions as observed in allergic diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic dermatitis and the like. Therefore, blocking the interaction of PGD 2 with its receptors is considered a useful therapeutic strategy for the treatment of such diseases.
  • WO 01/79169 discloses (tetrahydrocarbazol-l-y ⁇ acetic acid derivatives as PGD 2 receptor antagonists.
  • GB 2388540 (Bayer AG) discloses the use of ramatroban ((3i?)-3-(4-fluorobenzene- sulfonamido)-l,2,3,4-tetrahydrocarbazole-9-propionic acid), a TxA2 receptor (also referred to as "TP receptor") antagonist with additional antagonistic activity on CRTH2, for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjunctivitis.
  • TP receptor also referred to as "TP receptor”
  • WO 03/097598 and WO 03/097042 disclose Ramatroban analogues with CRTH2 antagonistic activity. Ulven et al, in J. Med. Chem. 2005, 48(4), 897-900 disclose further ramatroban analogues.
  • the compounds of the invention are structurally different from corticosteroids, antihistamines, leukotriene antagonists or beta-adrenergic agonists.
  • Description of the invention: i) The present invention relates to (3-amino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid compounds of the Formula I:
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen, Ci_ 5 -alkyl, Ci_ 5 -alkoxy, alkenyl (especially allyl or vinyl), halogen, nitro, cyano, halo-Ci_ 6 -alkoxy, halo-Ci_ 6 -alkyl, Ci_ 6 -alkylsulfonyl, or formyl;
  • R represents hydrogen, alkenyl (especially allyl or vinyl), Ci_ 6 -alkyl, cycloalkyl-Ci_ 4 -alkyl, Ci_ 3 -alkoxy-Ci_ 4 -alkyl, aryl-Ci_ 4 -alkyl, or aryloxy-Ci_ 4 -alkyl (especially R 5 represents hydrogen, Ci_ 6 -alkyl, cycloalkyl-Ci_ 4 -alkyl, Ci_ 3 -alkoxy-Ci_ 4 -alkyl, aryl-Ci_ 4 -alkyl, or aryloxy-Ci_ 4 -alkyl); wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 2 -alkylendioxy, Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluor
  • R represents Ci_ 9 -alkylaminocarbonyl; Ci_ 9 -alkylaminothiocarbonyl; Ci_ 9 -alkylcarbonyl; Ci_ 9 -alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; arylaminothiocarbonyl; aryl- C i_ 3 -alkoxy-C i_ 3 -alkoxycarbonyl; aryl-C i_ 3 -alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl; arylcarbonyl; arylcarbonyl- Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 3 -alkylcarbonyl; arylsulfonylaminocarbony
  • the invention relates to compounds of Formula I according to embodiment i), wherein
  • R 5 represents hydrogen, alkenyl (especially allyl or vinyl), or Ci_ 6 -alkyl
  • R 6 represents Ci_ 9 -alkylaminocarbonyl, Ci_ 9 -alkylaminothiocarbonyl, Ci_ 9 -alkylcarbonyl, Ci_ 9 -alkoxycarbonyl, arylalkenylcarbonyl, arylaminocarbonyl, arylaminothiocarbonyl, aryl- C i_ 3 -alkoxy-C i_ 3 -alkoxycarbonyl, aryl-Ci_ 3 -alkoxycarbonyl, aryl-C i_ 3 -alkylaminocarbonyl, aryl-Ci_ 3 -alkylcarbonyl, aryl-C i_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl, arylcarbonyl, arylcarbonyl- Ci_ 4 -alkylcarbonyl, aryloxy-Ci_ 3 -alkylcarbonyl, arylsulfonylamino
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen; Ci_ 5 -alkyl, especially methyl, or isopropyl; Ci_ 5 -alkoxy, especially methoxy; alkenyl, especially allyl or vinyl; halogen, especially fluoro, or chloro; halo-Ci_ 6 -alkyl, especially trifluoromethyl; or Ci_ 6 -alkylsulfonyl, especially methanesulfonyl; R 5 represents hydrogen; alkenyl, especially ethenyl, or 2-propenyl; or Ci_ 6 -alkyl, especially methyl, ethyl, or propyl; and
  • R 6 represents Ci_ 9 -alkylaminocarbonyl, such as butylaminocarbonyl; Ci_ 9 -alkylcarbonyl, such as propylcarbonyl, isobutylcarbonyl, hexylcarbonyl, or nonylcarbonyl; Ci_ 9 -alkoxycarbonyl, such as propoxycarbonyl, te/t-butoxycarbonyl, or isobutoxycarbonyl; arylalkenylcarbonyl, such as naphthalenylethenylcarbonyl (especially 2-naphthalen-2-yl- ethenylcarbonyl), or phenylethenylcarbonyl; arylaminocarbonyl, such as naphthalenaminocarbonyl (especially naphthalen-1-aminocarbonyl), or phenylaminocarbonyl; aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkoxycarbonyl, such as
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to iii), wherein R 1 represents hydrogen, or halogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to iv), wherein R 2 represents hydrogen, trifluoromethyl, or halogen (especially hydrogen, or halogen).
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to v), wherein R 3 represents hydrogen, or halogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to vi), wherein R 4 represents hydrogen, alkenyl (especially allyl or vinyl), halogen (especially chloro or bromo), Ci_ 6 -alkylsulfonyl (especially methanesulfonyl); especially hydrogen or halogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to vii), wherein R 1 , R 3 and R 4 represent hydrogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to viii), wherein R 2 represents fluoro.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen, Ci_6-alkyl (especially Ci_ 3 -alkyl), cycloalkyl-Ci_ 4 -alkyl (especially cyclopropylmethyl), Ci_ 3 -alkoxy- Ci_ 4 -alkyl (especially 2-methoxyethyl), aryl-Ci_ 4 -alkyl (especially naphthylmethyl, or preferably phenyl-C 2 - 3 -alkyl), or aryloxy-Ci_ 4 -alkyl (especially phenoxy ethyl); wherein aryl (especially phenyl) is unsubstituted (preferred), or mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_4-alkyl, halogen, trifluor
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen; Ci_3-alkyl (especially methyl); cyclopropylmethyl; 2-methoxyethyl; phenyl-C 2 - 3 -alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted (preferred), or mono-substituted with a group selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl).
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents Ci_3-alkyl (especially methyl); cyclopropylmethyl; 2-methoxyethyl; phenyl-C 2 - 3 -alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted (preferred), or mono-substituted with a group selected from Ci_ 2 -alkylendioxy, Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl).
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen, Ci_ 3 -alkyl (especially methyl), cyclopropylmethyl, or 2-methoxyethyl; especially cyclopropylmethyl, or 2-methoxyethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen, methyl, ethyl, or n-propyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents phenyl-C2-3-alkyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents Ci_9-alkylaminocarbonyl; Ci_ 9 -alkylcarbonyl; Ci_ 9 -alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl- C i_ 3 -alkoxy-C i_ 3 -alkoxycarbonyl; aryl-C i_ 3 -alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl; arylcarbonyl; arylcarbonyl- Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 3 -alkylcarbonyl; arylcarbony
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-
  • Ci_ 3 -alkylcarbonyl cycloalkyl-Ci_ 3 -alkylcarbonyl; diaryl-Ci_ 3 -alkylcarbonyl; aryl-
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-Ci_3-alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryloxy-Ci_ 3 -alkylcarbonyl; diaryl- Ci_ 3 -alkylcarbonyl; or R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl, and R 7 represents arylaminocarbonyl, or C i_ 6 -alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-Ci_2-alkoxycarbonyl; aryl-Ci_ 2 -alkylaminocarbonyl; aryl-Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 2 -alkylcarbonyl; or diaryl-C 2 - 3 -alkylcarbonyl; or R 7 -C 2 - 4 -alkylcarbonyl, wherein the bridging C 2 - 4 -alkyl group may additionally be mono-substituted with aryl, and R 7 represents arylaminocarbonyl, or
  • C i_ 4 -alkylaminocarbonyl wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 2 -alkylendioxy, Ci_ 6 -alkoxy, Ci_ 6 -alkyl, Ci_ 6 -alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl- Ci_ 2 -alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_ 6 -alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-Ci_2-alkoxycarbonyl; aryl-Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 2 -alkylcarbonyl; or diaryl-C 2 - 3 -alkylcarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 2 -alkylendioxy, Ci_ 6 -alkoxy, Ci_ 6 -alkyl, Ci_ 6 -alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxii), wherein, in case R 6 represents a group which contains aryl, the aryl group is phenyl which unsubstituted, or mono- or di-substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents Ci_4-alkylcarbonyl (especially acetyl); or aryl-C 2 - 4 -alkylcarbonyl, wherein aryl is unsubstituted, mono- or di- substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • R 6 represents Ci_4-alkylcarbonyl (especially acetyl); or aryl-C 2 - 4 -alkylcarbonyl, wherein aryl is unsubstituted, mono- or di- substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-C 2 _ 4 -alkylcarbonyl, wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxv), wherein, in case R 6 represents a group which contains a carbonyl group and one or more aryl moieties, said group is such that it contains a bridging group between the carbonyl group and said aryl moiety (moieties) of said R 6 , wherein the carbonyl moiety and at least one of the aryl moieties are directly attached to different atoms of said bridging group.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxv), wherein, in case R 6 represents a group which contains a carbonyl group and exactly one aryl moiety, said group is such that it contains a bridging group between the carbonyl group and said aryl moiety of said R 6 , wherein the carbonyl moiety and the aryl moiety are directly attached to the same atom of said bridging group.
  • a further embodiment of the invention relates to compounds of Formula I according to embodiment i), wherein R 1 represents hydrogen, or halogen;
  • R 2 represents hydrogen, trifluoromethyl, or halogen
  • R 3 represents hydrogen, or halogen
  • R 4 represents hydrogen, halogen (especially chloro or bromo), or Ci_ 6 -alkylsulfonyl
  • R 5 represents hydrogen, C ⁇ -alkyl, cycloalkyl-Ci_ 4 -alkyl, Ci_ 3 -alkoxy-Ci_ 4 -alkyl, aryl-
  • Ci_ 4 -alkyl or aryloxy-Ci_ 4 -alkyl; wherein aryl is unsubstituted, mono-substituted with a group selected from trifluoromethyl; and
  • R 6 represents Ci_ 9 -alkylaminocarbonyl; Ci_ 9 -alkylcarbonyl; Ci_ 9 -alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl-C ⁇ -alkoxy-Ci-s-alkoxycarbonyl; aryl-Ci_3- alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryl-Ci_ 3 -alkoxy- Ci_ 3 -alkylcarbonyl; arylcarbonyl; arylcarbonyl-Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 3 - alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl-Ci.s-alkylcarbonyl; diaryl-Ci_ 3 - alkylcarbon
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxviii), wherein the position C(3) of the tetrahydrocarbazole ring of Formula I is (5)-configurated.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxviii), wherein the position C(3) of the tetrahydrocarbazole ring of Formula I is (i?)-conf ⁇ gurated.
  • Any reference to a compound of Formula I is to be understood as referring also to salts (especially pharmaceutically acceptable salts) of a compound of Formula I, as appropriate and expedient.
  • pharmaceutically acceptable salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • bridging group or "bridging atom” as used herein means a group or atom that is placed between two distinct moieties of the molecule.
  • bridging groups are the bridging Ci_ 6 -alkyl group in an aryl- Ci_ 6 -alkylcarbonyl group which is placed between the aryl and the carbonyl moiety; the bridging Ci_ 4 -alkyl group in an aryl-Ci_ 4 -alkyl group, which is placed between the aryl moiety and the parent molecular moiety; or the bridging Ci_ 4 -alkyl group in an R 7 -Ci_ 4 -alkylcarbonyl group which is placed between the R 7 -group and the carbonyl moiety.
  • bridging atoms is the bridging carbon atom of a methylene (-CH 2 -) group in a benzyloxy or benzylamino group, which is placed between the phenyl ring and the oxygen atom, or the phenyl ring and the nitrogen atom, respectively.
  • alkyl refers to a saturated aliphatic group including a straight or branched hydrocarbon chain containing the indicated number of carbon atoms, for example Ci_ 9 -alkyl, i.e. an alkyl having 1-9 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, ⁇ o-propyl, n-butyl, tert-butyl, ⁇ o-butyl (or also referred to as "2-methylpropyl"), n-pentyl (also referred to as "n-amyl”), ⁇ o-pentyl (also referred to as " ⁇ o-amyl”), n-hexyl, n-heptyl, and n-octyl.
  • Preferred are methyl, ethyl, n-propyl, ⁇ o-propyl, n-butyl, and ⁇ o-butyl.
  • Most preferred are methyl, ethyl, n-propyl, and ⁇ o-propyl.
  • a bridging Ci_ 6 -alkyl group as used in "aryl-Ci_ 6 -alkylcarbonyl" as defined for R 6 preferably means a C 2 _ 4 -alkyl group, whereby the aryl moiety and the carbonyl moiety are preferably attached to two different carbon atoms of the bridging C2-4-alkyl group.
  • Preferred examples of bridging Ci_ 6 -alkyl groups as used in R 6 being aryl-Ci_ 6 -alkylcarbonyl are ethane- 1,2-diyl, propane- 1,2-diyl, propane- 1, 3 -diyl, and 2 -methyl-propane- 1,2-diyl.
  • a bridging Ci_ 6 -alkyl group as used in "aryl-Ci_ 6 -alkylcarbonyl" as defined for R 6 means the respective Ci_6-alkyl group, whereby the aryl moiety and the carbonyl moiety preferably are attached to the same carbon atom of the bridging Ci_ 6 -alkyl group.
  • Examples of such bridging Ci_ 6 -alkyl groups as used in R 6 being aryl- Ci_ 6 -alkylcarbonyl are a methylene group (preferred) and ethane- 1,1 -diyl.
  • a bridging Ci_ 3 -alkyl group as used in "diaryl-Ci_ 3 -alkylcarbonyl" as defined for R 6 preferably means a C2-3-alkyl group, whereby the carbonyl moiety and at least one of the aryl groups are preferably attached to two different carbon atoms of the bridging C 2 -3-alkyl group.
  • Preferred examples of such bridging Ci_ 3 -alkyl groups as used in R 6 being diaryl- Ci_ 3 -alkylcarbonyl are ethane- 1,2,2-triyl, and ethane- 1,1,2-triyl.
  • a bridging Ci_ 4 -alkyl group as used in "R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl" as defined for R 6 preferably means a C 2 _ 4 -alkyl group (particularly, if the additional aryl substituent is present, it means propane- 1, 2, 3-triyl) whereby the group R 7 , the carbonyl moiety, and the aryl substituent (if present) preferably are attached to two (three, if the additional aryl substituent is present) different carbon atoms of the bridging C 2 - 4 -alkyl group.
  • Examples of bridging Ci_ 4 -alkyl groups as used in R 6 being "R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl" are ethane- 1,2-diyl, propane- 1,2-diyl, propane- 1, 3 -diyl, 2-phenyl-propane-l,3-diyl, and l-phenyl-propane-2,3- diyl; preferred are 2-phenyl-propane-l,3-diyl, and l-phenyl-propane-2,3-diyl, especially 1 -phenyl-propane-2,3-diyl.
  • a bridging Ci_ 4 -alkyl group as used in R 6 being "R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 4 -alkyl group may additionally be disubstituted with hydroxy" is 1 ,2-dihydroxyethane- 1 ,2-diyl.
  • R a -Rd refer to substituents, each individually and independently selected from hydrogen and alkyl.
  • Representative examples of alkenyl include, but are not limited to, ethenyl (also referred to as "vinyl”), 2-propenyl (also referred to as "allyl”), 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl, especially ethenyl or 2-propenyl.
  • Ci_ 2 -alkylendioxy refers to an -O(CH2) n O- group, wherein n is 1 or 2, and wherein the oxygen atoms are attached to two adjacent carbon atoms of the parent molecular moiety, preferably the two adjacent carbon atoms of a phenyl ring.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen bridge.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexyloxy, especially methoxy.
  • alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and iso-butoxycarbonyl, especially methoxy.
  • R 6 representing alkoxycarbonyl preferably means n-propoxycarbonyl, and ⁇ o-butoxycarbonyl.
  • alkylcarbonyl as used herein, alone or in any combination, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. Further examples are l-oxo-2-methyl-butyl, and 3, 3 -dimethyl- 1-oxopropyl. Preferred are acetyl, 1-oxopropyl, 1-oxobutyl, l-oxo-2-methyl- butyl, and 3, 3 -dimethyl- 1-oxopropyl.
  • alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
  • alkylsulfonyl include, but are not limited to, methanesulfonyl and ethanesulfonyl, preferably methanesulfonyl.
  • aminocarbonyl also referred to as “carbamoyl” as used herein, alone or in any combination, refers to an amino group attached to the parent molecular moiety through a carbonyl group.
  • aryl or "aryl group”, as used herein, alone or in any combination, refers to an aromatic carbocyclic group from 6 to 14 carbon atoms having a single ring or multiple condensed rings, and preferably refers to a phenyl or naphthyl, very preferably to a phenyl group.
  • An aryl group is preferably unsubstituted. In another embodiment the aryl group may be substituted as specifically described in the embodiments of the present invention.
  • an aryl group is mono- or di-substituted
  • preferred but not limiting examples are 4-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 2,5-bis-trifluoromethyl-phenyl, 3,5-bis- trifluoromethyl-phenyl, 3 -trifluoromethoxy -phenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-te/t.-butylphenyl, 4-fluorophenyl, 3 -fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, 4-iodophenyl, 3-bromophenyl, 2-
  • arylalkenyl refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3-phenylpropen-2-yl, and 2- naphth-2-ylethenyl.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxygen bridge.
  • arylsulfonyl refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.
  • carbonyl as used herein, alone or in any combination, refers to a -C(O)- group.
  • thiocarbonyl refers to a -C(S)- group.
  • cyano refers to a -C ⁇ N group.
  • cycloalkyl refers to a saturated cyclic hydrocarbon moiety containing 3-10 carbon atoms (for example C 3 _ 6 -cycloalkyl means a cycloalkyl having 3 to 6 carbon atoms), preferably a cyclopentyl or cyclohexyl radical, whereby said radicals, especially the cyclopentyl radical, may be substituted with an annellated benzene ring.
  • said benzene ring may be mono-, or di- substituted, wherein the substituent(s) are independently selected from Ci_4-alkyl, Ci_4-alkoxy, and halogen (especially Ci_4-alkoxy).
  • cycloalkyl group is used as a bridging group as for example in an "aryl-C 3 - 6 -cycloalkylcarbonyl" group as defined for R 6 , it is preferably a cyclopropane-diyl, cyclopentane-diyl or cyclohexane-diyl radical (especially cyclopropane- 1 ,2-diyl) said radical being preferably unsubstituted.
  • haloalkyl refers to an alkyl group having at least one hydrogen atom replaced with a halogen atom.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl, preferably trifluoromethyl.
  • haloalkoxy refers to an alkoxy group having at least one hydrogen atom replaced with a halogen atom.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy, preferably trifluoromethoxy.
  • heterocyclyl refers to a monocyclic, bicyclic or polycyclic non-aromatic ring system containing up to 15 ring atoms (preferably 5 to 10 ring atoms), at least one of these being a heteroatom, preferably one to three heteroatoms, independently selected from nitrogen, oxygen or sulfur, preferably nitrogen.
  • This ring system may be saturated, partially saturated, or unsaturated, and preferably contains one or two ring heteroatoms selected from nitrogen.
  • Representative examples of heterocyclyl include, but are not limited to, dihydroindolyl (especially dihydroindol-2-yl) and chromane (especially chroman-3-yl).
  • heteroaryl as used herein, alone or in any combination, has the meaning as defined for heterocyclyl above, with the difference that the ring system is aromatic.
  • heteroarylalkyl refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group.
  • Representative examples of heteroarylalkyl include, but are not limited to, thienylalkyl (especially thien-2-ylalkyl), isoxazolylalkyl (especially 3-chloro-isoxazole-5-ylalkyl), pyridylalkyl (especially pyridine-3-ylalkyl), pyrimidylalkyl (especially pyrimidine- 2-ylalkyl), indolylalkyl (especially indol-3-ylalkyl), and benzoimidazolylalkyl (especially benzoimidazol-2-ylalkyl).
  • heteroarylcarbonyl refers to a heteroaryl group attached to the parent molecular moiety through a carbonyl group.
  • a representative example of heteroarylcarbonyl includes, but is not limited to, indolylcarbonyl (especially indol-2-ylcarbonyl).
  • heteroarylamino refers to a heteroaryl group attached to the parent molecular moiety through an amino group.
  • a representative example of heteroarylamino includes, thiadiazolylamino (especially 1,3,4- thiadiazol-2-yl-amino).
  • heterocyclylcarbonyl refers to a heterocyclyl group attached to the parent molecular moiety through a carbonyl group.
  • a representative example of heterocyclylcarbonyl includes, dihydroindolylcarbonyl (especially dihydroindol-2-ylcarbonyl) and chromanecarbonyl (especially chroman- 3-ylcarbonyl).
  • hydroxy or "hydroxyl” as used herein, alone or in any combination, refers to an -OH group
  • nitro refers to a -NO 2 group.
  • oxy refers to an -O- group.
  • sulfonyl as used herein, alone or in any combination, refer to an -S(O) 2 - group.
  • acyl refers to groups containing a carbonyl group that is linked to a carbon atom such as Ci_ 9 -alkylcarbonyl, arylalkenylcarbonyl, aryl-Ci_ 6 -alkylcarbonyl, aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl, arylcarbonyl, arylcarbonyl-Ci_ 4 -alkylcarbonyl, aryloxy- Ci_ 3 -alkylcarbonyl, cycloalkyl-Ci_ 3 -alkylcarbonyl, diaryl-Ci_ 3 -alkylcarbonyl, heterocyclylcarbonyl, heteroaryl-Ci_ 3 -alkylcarbonyl, heteroarylcarbonyl, aryl- C 3 - 6 -cycloalkylcarbonyl, cycloalkylcarbonyl, or R 7 -Ci_ 4 -alkyl
  • acylamino refers to an acyl group as described before that is linked to the parent molecular moiety through a nitrogen atom.
  • ureido refers to groups such as Ci_ 9 -alkylaminocarbonyl, arylaminocarbonyl, or aryl-Ci_ 3 -alkylaminocarbonyl that are linked to the parent molecular moiety through a nitrogen atom.
  • oxycarbonylamino refers to groups such as Ci_9-alkoxycarbonyl, aryl-Ci_ 3 -alkoxycarbonyl, or aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkoxycarbonyl that are linked to the parent molecular moiety through a nitrogen atom.
  • the compounds of Formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • the compounds of the present invention have useful, in particular pharmacologically useful, properties. They bind to the CRTH2 receptor and thus modulate the effects of endogenous PGD 2 .
  • the compounds according to Formula I may be used for the preparation of a medicament, and are suitable, for the prevention and/or treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia- reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg-Str
  • a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I may be used for the preparation of a medicament, and is suitable, for the prevention and/or treatment of diseases selected from the group consisting of both chronic and acute allergic/immune diseases/disorders such as those mentioned in the paragraph before, such as especially allergic asthma, rhinitis, allergic rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • diseases selected from the group consisting of both chronic and acute allergic/immune diseases/disorders such as those mentioned in the paragraph before, such as especially allergic asthma, rhinitis, allergic rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
  • the compounds of Formula I may be used as standard or reference compounds in tests or assays involving the modulation of the CRTH2 receptor.
  • Such compounds could be made commercially available for use as a reference, quality standard or control, for example in pharmaceutical research when developing new assays or protocols related to CRTH2 receptor activity.
  • compounds of Formula I modulate the PGD 2 activation of the CRTH2 receptor.
  • the biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays.
  • the ability of the compounds of Formula I to bind to the CRTH2 receptor may be measured by methods similar to those described in the literature (Arimura
  • a functional assay with cells expressing the human CRTH2 (hCRTH2) receptor may be used to detect changes in the levels of intracellular calcium concentration following compound treatment. After addition of the compound, the cells are challenged with PGD 2 . In a Fluorescent Imaging Plate Reader (FLIPRTM, Molecular Devices, Sunnyvale, California), fluorescence emission is recorded during both additions, emission peak values above base level after PGD 2 addition are exported, and normalized to low controls (no PGD 2 ) and high controls (no active compound).
  • FLIPRTM Fluorescent Imaging Plate Reader
  • the relative values of the remaining activity are used to determine IC50 values by curve fitting the data to a single site to a four- parameter logistic sigmoid dose response curve of the equation (A+((B-A)/(l+((C/x) ⁇ D)))).
  • the ability of the compounds to modulate PGD 2 induced changes of intracellular calcium levels via CRTH2 receptor activation may be measured by methods known to one skilled in the art or by the assay described below in the experimental part.
  • the present invention relates also to pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; to the use of such pharmaceutical compositions for the therapeutic, in a broader aspect of the invention also prophylactic, treatment of the diseases/disorders mentioned herein; to the compounds of Formula I, or pharmaceutically acceptable salts thereof, for use as a medicament; and to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the prevention and/or treatment of the diseases/disorders mentioned herein.
  • compositions according to the invention are those for enteral administration, such as nasal, buccal, rectal, dermal or, especially oral administration, and for parenteral administration, such as intramuscular, intravenous or subcutaneous, intrasternal, intravitreal, injection or infusion, to warm-blooded animals, especially humans.
  • Such compositions comprise an effective dose of the pharmaceutically active ingredient, alone or together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual conditions, individual pharmacokinetic data, the disease/disorder to be treated and the mode of administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of Formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the invention also relates to a method for the prevention or treatment of diseases/disorders that respond to an inhibition of the CRTH2 receptor in particular to a method for the prevention or treatment of the diseases/disorders mentioned herein, said methods comprising administering to a patient a pharmaceutically active amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the invention is a process for the preparation of compounds of Formula I.
  • Compounds according to Formula I of the present invention can be prepared according to the sequence of reactions outlined in the schemes below wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined for Formula I. Other abbreviations used are defined in the experimental section. In some instances the generic groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 might be incompatible with the assembly illustrated in the schemes below and, therefore, will require the use of protecting groups (PG).
  • PG protecting groups
  • PG when used as amino-protecting group, preferably refers to a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably tert- butoxycarbonyl.
  • L refers to a leaving group, such as activated (for examples as mesylate, active ester etc.) or non-activated hydroxy, or halo, in particular chloro or bromo.
  • R and R' independently refer to a Ci_ 4 -alkyl group, preferably ethyl or tert-hvXyl, whereby when R is present R is preferably ethyl and R' is preferably tert. -hvXyX.
  • compounds of Formula I are obtained from an ester of Structure 1, wherein R represents Ci_4-alkyl, preferably ethyl, or tert-bv ⁇ yl, by hydrolysis of the ester group using routine procedures, for example stirring an intermediate of Structure 1 with aq. lithium, sodium or potassium hydroxide in an organic co-solvent such as an alcohol, like MeOH or EtOH; THF; acetone; MeCN; or TFA, respectively.
  • an organic co-solvent such as an alcohol, like MeOH or EtOH; THF; acetone; MeCN; or TFA, respectively.
  • An intermediate of Structure 1 is obtained by reacting an intermediate of Structure 2a or 2b, or a salt thereof, such as the hydrochloride salt, with a reagent of Formula L-R 6 , wherein R 6 is as defined for Formula I and L is a leaving group as defined before.
  • R 6 transferring reagent of Structure L-R 6 may be a chloroformate; or an acyl halide, preferably an acid chloride, or acid bromide, used as such; or generated in situ from the corresponding commercially available or well known carboxylic acid with an activating reagent, such as a halogenating reagent under conditions known to a skilled person, preferably by means of oxalyl chloride or phosphorous oxychloride; or an acyl anhydride, transferring R 6 in the presence of a base, such as Et 3 N, DIEA, JV-ethyl-morpholine, TV-methylpiperidine, or pyridine, in a suitable solvent, such as THF, or DCM.
  • a base such as Et 3 N, DIEA, JV-ethyl-morpholine, TV-methylpiperidine, or pyridine
  • an intermediate of Structure 2a or 2b is condensed with a commercially available or well known carboxylic acid in the presence of a coupling reagent, such as DCC, diisopropylcarbodiimide, HATU and the like, in the presence of a base described hereinabove, to form an intermediate of Structure 1.
  • a coupling reagent such as DCC, diisopropylcarbodiimide, HATU and the like
  • an intermediate of Structure 2a or 2b is reacted with a commercially available isocyanate or isothiocyanate in the presence of a base to form an intermediate of Structure 1.
  • intermediates of Structure 1, wherein R 4 represents an Ci_ 5 -alkyl, allyl, vinyl, or a methanesulfonyl group is obtained by reacting intermediates of Structure 2c wherein R 4 represents halogen, preferably I or Br, or a methanesulfonyloxy, or a toluenesulfonyloxy group, with reagents such as tetramethyltin, allyltributyltin, a complex of vinylboronic anhydride and pyridine together with a base, such as K 2 CO 3 , in the presence of a palladium catalyst such as tetr ⁇ Hs(triphenylphosphine)palladium(0), or the like, or sodium methanesulfinate in the presence of copper (I) iodide, respectively, in a polar aprotic solvent such as DMF, or DME, or NMP, at a temperature between 6O 0 C and 130
  • a substituent R in an intermediate of Structure 2a is obtained by reacting an intermediate of Structure 2b with the respective aldehyde in a solvent such as DCM or the like in presence of a reducing agent, such as sodium triacetoxyborohydride, and a base, such as DIEA.
  • a reducing agent such as sodium triacetoxyborohydride
  • a base such as DIEA
  • an intermediate of Structure 2a wherein R 5 is not hydrogen, is obtained from an intermediate of Structure 2b via a sulfonamide of Structure 3a.
  • an intermediate of Structure 2b is reacted with/?-nitrobenzenesulfonyl chloride in a solvent such as DCM, THF or another suitable organic solvent, in the presence of a base, such as DIEA, with or without a catalytic amount of N, ⁇ /-dimethyl-aminopyridine, to afford the desired sulfonamide of Structure 3a.
  • the sulfonamide of Structure 3a is easily alkylated with the respective commercially available or well known alkylating agent R 5 -L, with K 2 CO 3 or any other suitable base, in an organic solvent, such as toluene, preferably in the presence of a phase transfer agent, such as tetrabutylammonium bromide in accordance to a procedure described in the literature (C. Pena et al, Tetrahedron Lett. 2005, 46, 2783-2787).
  • a methyl group is introduced by reaction of a sulfonamide of Structure 3a either with methyl iodide or with diazomethane dissolved in diethylether.
  • the sulfonamide of Structure 3b is treated in a typical procedure according to S.C. Miller and coworker (J. Am. Chem. Soc. 1997, 119, 2301-2302) with a thiol, such as thiophenol, or thioacetic acid, in the presence of a base, such as DBU or the like, in a suitable organic solvent, such as DMF, to remove the sulfonamido group, furnishing an intermediate of Structure 2a.
  • a thiol such as thiophenol, or thioacetic acid
  • An intermediate of Structure 2b is obtained after removal of the protective group (PG) from an intermediate of Structure 2c, applying reaction conditions known to a skilled person.
  • the PG is a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably te/t-butoxycarbonyl.
  • An intermediate of Structure 2c is generated by reacting an intermediate of Structure 4 with a compound of Formula L-CH 2 CO 2 R wherein R and L are as defined before, in the presence of a base, such as cesium carbonate, sodium hydride, potassium tert-butanolate or the like, in a suitable solvent, such as acetone, MeCN, THF or dioxane.
  • a base such as cesium carbonate, sodium hydride, potassium tert-butanolate or the like
  • a suitable solvent such as acetone, MeCN, THF or dioxane.
  • Suitable L is a leaving group such as halo, in particular bromo or chloro; mesyloxy or tosyloxy.
  • the compound of Formula L-CH 2 CO 2 R is ethyl bromoacetate.
  • an intermediate of Structure 4 is obtained through protection of the amino group in a tetrahydrocarbazol-3-ylamine of Structure 7 with a hereinabove described PG applying methods known to a skilled person.
  • a coupling reagent such as DCC, diisopropylcarbodiimide, ⁇ ATU or the like
  • a compound of Structure 8a wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl is obtained by treating a respective compound of Structure 8b, wherein R' represents Ci_4-alkyl, preferentially tert-butyl, as a protecting group, with reaction with TFA in DCM or hydrochloric acid in an organic solvent, such as dioxane, diethylether, AcOEt, or the like, at room temperature.
  • R represents Ci_4-alkyl
  • a compound of Structure 8b is obtained by reacting a compound of Structure 2a or 2b with the corresponding compound of Structure 9, wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl, which are commercially available or synthesized according to well known methods such as enolate alkylation (see for example: J. Org. Chem. 1986, 51(6), 938-940), in the presence of a coupling reagent, such as DCC, diisopropylcarbodiimide, HATU, or the like, in the presence of a base such as Et 3 N, DIEA, or the like, in a solvent such as DCM or DMF.
  • a coupling reagent such as DCC, diisopropylcarbodiimide, HATU, or the like
  • a base such as Et 3 N, DIEA, or the like
  • the enantiomers can be separated using methods known to the one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as Et 3 N, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • EtOH EtOH
  • eluent B hexane
  • HPLC/MS analyses are performed on a Waters 2795 Alliance HPLC instrument, equipped with a Waters 996 Photodiode Array Detector and a Micromass ZQTM Waters mass spectrometer (electron spray ionization), detection at 200-400 nm (LC-I and LC-2), or on a Agilent 1100 system, equipped with a Dionex P580 binary pump, a Dionex PDA-100 Photodiode Array Detector and a Finnigan AQA mass spectrometer (LC-3).
  • - LC-2 Analytical HPLC on a Zorbax ® SB-AQ column (4.6x50 mm, 5 ⁇ m, Agilent); Linear gradient of water/ 0.06% formic acid (A) and MeCN/ 0.06% formic acid (B) from 5% to 95% B over 1 min; flow rate 3 ml/min, detection at 215 nm.
  • Preparative HPLC/MS purifications are performed on a Waters HPLC system, equipped with a Waters 600 controller, a Waters 2767 sample manager, a Waters 996 Photodiode Array Detector, and a Micromass ZQTM Waters mass spectrometer (electron spray ionization), detection at 200-400 nm, using a Zorbax® PrepHT SB.
  • a Waters HPLC system equipped with a Waters 600 controller, a Waters 2767 sample manager, a Waters 996 Photodiode Array Detector, and a Micromass ZQTM Waters mass spectrometer (electron spray ionization), detection at 200-400 nm, using a Zorbax® PrepHT SB.
  • Table 1 Listed in Table 1 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding compound of Structure 1 as starting material. Table 1 Example Compound of Formula I Formula t R [min] MS
  • Table 2a Listed in Table 2a below are further ethyl [3-ureido-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetate derivatives of Structure 1, prepared according to the above mentioned method, with the corresponding compound of Structure 2a or 2b as starting material.
  • Table 2a Listed in Table 2a below are further ethyl [3-ureido-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetate derivatives of Structure 1, prepared according to the above mentioned method, with the corresponding compound of Structure 2a or 2b as starting material.
  • a solution of a hydrochloride of the appropriate intermediate of Structure 2a or 2b (0.075 mmol) and DIEA (0.15 mmol) in a 4:1 mixture (2 ml) of dry DMF and T ⁇ F is added dropwise to a stirred solution of the appropriate carboxylic acid (0.113 mmol), HATU (0.15 mmol) and DIEA (0.15 mmol) in a 4:1 mixture (2 ml) of dry DMF and THF at 0 0 C.
  • the mixture is stirred at rt for 1 h, or overnight, then sat. NaHCO 3 solution is added. After phase separation, the aq. layer is extracted three times with DCM. The combined org. phases are evaporated.
  • the crude ethyl (3-acylamido-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 is obtained with >50% yield and is either used as such in the next step or purified by prepaprative ⁇ PLC to give the pure ethyl (3-acylamino-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 with 13 to 95% yield.
  • Table 4 Listed in Table 4 below are crude ethyl (3-acylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetate derivatives of Structure 1, prepared according to the above mentioned methods (A) or (B), with the corresponding intermediate of Structure 2a or 2b as starting material. Table 4
  • Table 4a Listed in Table 4a below are further ethyl (3-acylamino-l,2,3,4-tetrahydro-9H-carbazol-9- yl)-acetate derivatives of Structure 1, prepared according to the above mentioned methods (A) or (B), with the corresponding intermediate of Structure 2a or 2b as starting material.
  • Table 4a Listed in Table 4a below are further ethyl (3-acylamino-l,2,3,4-tetrahydro-9H-carbazol-9- yl)-acetate derivatives of Structure 1, prepared according to the above mentioned methods (A) or (B), with the corresponding intermediate of Structure 2a or 2b as starting material.

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Abstract

La présente invention concerne des dérivés de l'acide (3-amino-1,2,3,4-tétrahydro-9H-carbazol-9-yl)-acétique de la Formule I (I) dans laquelle R1, R2, R3, R4, R5 et R6 sont tels que définis dans la description, et leur utilisation en tant que modulateurs des récepteurs de la prostaglandine, plus particulièrement comme modulateurs des récepteurs de la prostaglandine D2, dans le traitement de diverses maladies et troubles à médiation par la prostaglandine. La présente invention concerne également des compositions pharmaceutiques contenant ces composés et des procédés permettant de les préparer.
PCT/IB2007/053046 2006-08-07 2007-08-02 Dérivés de l'acide (3-amino-1,2,3,4-tétrahydro-9h-carbazol-9-yl)-acétique WO2008017989A1 (fr)

Priority Applications (19)

Application Number Priority Date Filing Date Title
US12/376,932 US8143304B2 (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9 H-carbazol-9-yl)-acetic acid derivatives
DK07805287.5T DK2051962T3 (da) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-eddikesyrederivater
KR1020097004370A KR101411820B1 (ko) 2006-08-07 2007-08-02 (3-아미노-1,2,3,4-테트라하이드로-9ｈ-카르바졸-9-일)-아세트산 유도체
CN2007800292169A CN101500996B (zh) 2006-08-07 2007-08-02 (3-胺基-1,2,3,4-四氢-9h-咔唑-9-基)-乙酸衍生物
MX2009001105A MX2009001105A (es) 2006-08-07 2007-08-02 Derivados del acido (3-amino-1,2,3,4-tetrahidro-9h-carbazol-9-il)- acetico.
EP07805287A EP2051962B1 (fr) 2006-08-07 2007-08-02 Dérivés de l'acide (3-amino-1,2,3,4-tétrahydro-9h-carbazol-9-yl)-acétique
CA2658986A CA2658986C (fr) 2006-08-07 2007-08-02 Derives de l'acide (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetique
SI200730818T SI2051962T1 (sl) 2006-08-07 2007-08-02 Derivati (3-amino-1,2,3,4-tetrahidro-9h-karbazol-9-il)-ocetne kisline
AT07805287T ATE530523T1 (de) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)- essigsäurederivate
ES07805287T ES2374321T3 (es) 2006-08-07 2007-08-02 Derivados del ácido (3-amino-1,2,3,4-tetrahidro-9h-carbazol-9-il)-acético.
AU2007282949A AU2007282949B8 (en) 2006-08-07 2007-08-02 (3-Amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid derivatives
BRPI0715179-9A BRPI0715179A2 (pt) 2006-08-07 2007-08-02 composto, composiÇço farmacÊutica e uso de um composto
JP2009523396A JP5220013B2 (ja) 2006-08-07 2007-08-02 （３−アミノ−１，２，３，４−テトラヒドロ−９ｈ−カルバゾール−９−イル）−酢酸誘導体
NZ574705A NZ574705A (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
PL07805287T PL2051962T3 (pl) 2006-08-07 2007-08-02 Pochodne kwasu (3-amino-1,2,3,4-tetrahydro-9h-karbazol-9-ilo)-octowego
IL196891A IL196891A (en) 2006-08-07 2009-02-04 Annals @@@ - Amino - @@@@@@@ - Tetrahydro - H9 - Carbazole - 9 - Yl) - Acetic Acid, Containing Pharmaceuticals
NO20090979A NO20090979L (no) 2006-08-07 2009-03-04 (3-amino-1,2,3,4-tetrahydro-9H-karbazol-9-yl)-eddiksyrederivater
HK09110028.6A HK1130062A1 (fr) 2006-08-07 2009-10-28
HR20120044T HRP20120044T1 (hr) 2006-08-07 2012-01-13 Derivati (3-amino-1,2,3,4-tetrahidro-9h-karbazol-9-il)-octene kiseline

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IB2006052723 2006-08-07
IBPCT/IB2006/052723 2006-08-07

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EP (2) EP2316824A1 (fr)
JP (1) JP5220013B2 (fr)
KR (1) KR101411820B1 (fr)
CN (1) CN101500996B (fr)
AR (1) AR062222A1 (fr)
AT (1) ATE530523T1 (fr)
AU (1) AU2007282949B8 (fr)
BR (1) BRPI0715179A2 (fr)
CA (1) CA2658986C (fr)
CL (1) CL2007002274A1 (fr)
CY (1) CY1112276T1 (fr)
DK (1) DK2051962T3 (fr)
ES (1) ES2374321T3 (fr)
HK (1) HK1130062A1 (fr)
HR (1) HRP20120044T1 (fr)
IL (1) IL196891A (fr)
MA (1) MA30696B1 (fr)
MX (1) MX2009001105A (fr)
MY (1) MY147588A (fr)
NO (1) NO20090979L (fr)
NZ (1) NZ574705A (fr)
PL (1) PL2051962T3 (fr)
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US20100190830A1 (en) 2010-07-29
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RU2009107889A (ru) 2010-09-20
CN101500996B (zh) 2012-07-04
ES2374321T3 (es) 2012-02-15
MA30696B1 (fr) 2009-09-01
CY1112276T1 (el) 2015-12-09
IL196891A0 (en) 2009-11-18
AU2007282949B2 (en) 2012-08-30
TW200817328A (en) 2008-04-16
JP5220013B2 (ja) 2013-06-26
SI2051962T1 (sl) 2012-02-29
KR20090047504A (ko) 2009-05-12
MX2009001105A (es) 2009-02-10
AU2007282949A1 (en) 2008-02-14
JP2010500337A (ja) 2010-01-07
US8143304B2 (en) 2012-03-27
RU2448092C2 (ru) 2012-04-20
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CA2658986A1 (fr) 2008-02-14
MY147588A (en) 2012-12-31
AR062222A1 (es) 2008-10-22
ATE530523T1 (de) 2011-11-15
EP2316824A1 (fr) 2011-05-04
PT2051962E (pt) 2012-01-10
CN101500996A (zh) 2009-08-05
HRP20120044T1 (hr) 2012-02-29
AU2007282949B8 (en) 2012-10-04
HK1130062A1 (fr) 2009-12-18
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BRPI0715179A2 (pt) 2013-06-11
EP2051962A1 (fr) 2009-04-29
PL2051962T3 (pl) 2012-03-30
NZ574705A (en) 2011-12-22
EP2051962B1 (fr) 2011-10-26
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DK2051962T3 (da) 2012-01-02
IL196891A (en) 2013-07-31

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